Reversal of Diabetes by Pdx1-VP16 and Pax4 Induced Islet Regeneration It has been demonstrated that endocrine pancreas has a potential to regeneration and the process could be facilitated by many factors like Exendin-4. The induction of endogenous beta cell regeneration could revolutionize diabetes therapy. Nonetheless, no robust regeneration-inducing protocol has been determined so far. Key pancreatic transcription factors such as Pdx1 and Pax4 has been demonstrated to reprogram stem cell in favor of endocrine pancreas differentiation. Understanding the factors and mechanisms involved n fi-cell regeneration will guide therapeutic efforts to augment fi-cell mass in patients with diabetes. Therefore, we hypothesize that in vivo delivery of pancreatic transcription factors (i.e., Pdx1-VP16 and Pax4) nto the pancreas of diabetic mice and nonhuman primates will promote islet cell regeneration and restore oancreatic endocrine function. In this study, we will blaze the trail to regeneration through the following approach: 1. To determine the effect of Pdx1-VP16 and Pax4 delivery on blood glucose levels and islet cell regeneration in a diabetic mouse model. 2. To determine the effects of Pdx1-VP16 and Pax4 on promoting islet cell regeneration in a spontaneous diabetic NOD mouse model in settings with and without control of autoimmunity. 3. To examine whether delivery of human Pdx1 by AAV8 vector to the pancreas of non-human primates (NHP) suffering from spontaneous T2DM can reverse hyperglycemia. It is possible that new therapeutic strategies may arise from harnessing pancreatic transcription factors in innovative ways in order to regenerate islets lost to diabetes.